‘Western’ liver damage difficult to reverse – mouse study

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Liver damage caused by the typical “Western diet” – one high in fat, sugar and cholesterol that’s common in developed countries such as the US – may be difficult to reverse even if diet is generally improved, a new study shows.

The research by scientists from Oregon State University, found that a diet with reduced fat and cholesterol helped, but did not fully resolve liver damage that had already been done – damage that in turn can lead to more serious health problems, such as cirrhosis or even cancer.

This study, done with laboratory animals, showed that diets low in fat and cholesterol could in fact aid with weight loss, improved metabolism and health. But even then, if the diet was still high in sugar there was much less liver recovery, the scientists concluded.

The findings are significant, scientists say, because liver problems such as non-alcoholic fatty liver disease are surging in the US, affecting 10%-35% of adults and an increasing number of children. The incidence of this problem can reach more than 60% in obese and type-2 diabetic populations.

“Many people eating a common American diet are developing extensive hepatic fibrosis, or scarring of their liver, which can reduce its capacity to function, and sometimes lead to cancer,” said Donald Jump, a professor in the OSU College of Public Health and Human Sciences, principal investigator with the Linus Pauling Institute, and corresponding author on this research.

“There’s a lot of interest in finding ways to help the liver recover from this damage, but this research suggests that diets lower in fat and cholesterol, even if they help you lose weight, are not enough,” Jump said. “For more significant liver recovery, the intake of sugar has to come down, probably along with other improvements in diet and exercise.”

The issues are both serious and complex, the researchers said. “Everyone recognises this is a serious problem,” said Kelli Lytle, an OSU doctoral candidate and lead author on this study. “We’re trying to find out if some of the types of dietary manipulation that people use, such as weight loss based on a low fat diet, will help address it. However, a common concern is that many ‘low-fat’ food products have higher levels of sugar to help make them taste better.”

Weight loss does appear to help address some of the problems associated with the Western diet, the research shows. But according to this study, a diet with continued high levels of sugar will significantly slow recovery of liver damage that has already been done.

Complications related to liver inflammation, scarring and damage are projected to be the leading cause of liver transplants by 2020, the researchers noted in their study. Such scarring was once thought to be irreversible, but more recent research has shown it can be at least partially reversed with optimal diet and when the stimulus for liver injury is removed.

In this report, scientists studied two groups of laboratory mice that had been fed a “Western diet” and then switched to different, healthier diets, low in fat and cholesterol. Both of the improved diets caused health improvements and weight loss. But one group that was fed a diet still fairly high in sugar – an amount of sugar comparable to the Western diet – had significantly higher levels of inflammation, oxidative stress and liver fibrosis.

More research is still needed to determine whether a comprehensive programme of diet, weight maintenance, exercise and targeted drug therapies can fully resolve liver fibrosis, the study concluded.

Abstract
Background
Non-alcoholic fatty liver disease (NAFLD) is a major public health burden in western societies. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is characterized by hepatosteatosis, inflammation, oxidative stress, and hepatic damage that can progress to fibrosis and cirrhosis; risk factors for hepatocellular carcinoma. Given the scope of NASH, validating treatment protocols (i.e., low fat diets and weight loss) is imperative.
Methods
We evaluated the efficacy of two diets, a non-purified chow (NP) and purified (low-fat low-cholesterol, LFLC) diet to reverse western diet (WD)-induced NASH and fibrosis in Ldlr-/- mice.
Results
Mice fed WD for 22–24 weeks developed robust hepatosteatosis with mild fibrosis, while mice maintained on the WD an additional 7–8 weeks developed NASH with moderate fibrosis. Returning WD-fed mice to the NP or LFLC diets significantly reduced body weight and plasma markers of metabolic syndrome (dyslipidemia, hyperglycemia) and hepatic gene expression markers of inflammation (Mcp1), oxidative stress (Nox2), fibrosis (Col1A, LoxL2, Timp1) and collagen crosslinking (hydroxyproline). Time course analyses established that plasma triglycerides and hepatic Col1A1 mRNA were rapidly reduced following the switch from the WD to the LFLC diet. However, hepatic triglyceride content and fibrosis did not return to normal levels 8 weeks after the change to the LFLC diet. Time course studies further revealed a strong association (r2 ≥ 0.52) between plasma markers of inflammation (TLR2 activators) and hepatic fibrosis markers (Col1A, Timp1, LoxL2). Inflammation and fibrosis markers were inversely associated (r2 ≥ 0.32) with diet-induced changes in hepatic ω3 and ω6 polyunsaturated fatty acids (PUFA) content.
Conclusion
These studies establish a temporal link between plasma markers of inflammation and hepatic PUFA and fibrosis. Low-fat low-cholesterol diets promote reversal of many, but not all, features associated with WD-induced NASH and fibrosis in Ldlr-/- mice.

Oregon State University material
PLOS One abstract


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